Brown and colleagues (Nature 1993) have cloned a novel calcium-sensing receptor (CaR) which is a member of the G protein-coupled receptor superfamily similar in structure to the metabotropic glutamate receptors. The CaR is expressed in a limited range of cell types including kidney, brain, thyroid C cells, and most prominently parathyroid cells. Mutations in the CaR identified in the human genetic disorder familial hypocalciuric hypocalcemia provide strong evidence for the physiologic importance of the receptor in calcium sensing generally and in regulation of parathyroid hormone secretion by extracellular ionized calcium in particular. We are studying several aspects of the receptor's structure and function. We have raised polyclonal antisera to several synthetic peptides corresponding to sequences in the large extracellular domain. These recognized the receptor on western blots and should be useful for a wide variety of studies. Development of monoclonal antibodies is planned with the long-range goal of being used as imaging reagents for parathyroid tumors in patients with failed neck explorations. We are also studying the coupling of the receptor to G proteins using transfection techniques, and by defining the normal complement of G protein alpha subunits in parathyroid cells.